Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a dismal prognosis. The poor prognosis is a direct result of the fact that potentially efficacious therapeutics cannot access all primary tumor and infiltrating GBM cells due to the blood-brain barrier (BBB) or blood-brain tumor barrier (BBTB). Our central hypothesis is that we can use novel high-frequency ultrasound (HIFU)-based techniques to remotely permeabilize the BBB and systemically delivery conventional chemotherapy and novel molecular targeted therapeutics to GBM, especially infiltrating cells that reside in predominantly normal brain. In addition to conventional HIFU techniques, we will use an innovative remote-controllable stem cell-based platform to allow us to non-invasively activate engineered stem cells to produce specific cytokines at the time and site of our choosing. To test these hypotheses, 2 specific aims will be performed: (Specific Aim 1) To demonstrate the feasibility of using image-guided HIFU remote activation to artificially induce TNF? and permeabilize the BBB and thereby allowing systemically administered therapeutics to access invasive GBM cells; (Specific Aim 2) To demonstrate anti-GBM efficacy of novel molecular targeted therapeutics after systemic infusion and HIFU- mediated BBB/BBTB focal permeability. Delivery of therapeutic agents through the BBB specifically to tumor cells but not to the surrounding normal brain tissue offers hope against GBM, an invariably fatal disease. Thus, this proposal has strong translational relevance.